Kavita Raj

A no-prophylaxis platelet-transfusion strategy for hematologic cancers.

BACKGROUND The effectiveness of platelet transfusions to prevent bleeding in patients with hematologic cancers remains unclear. This trial assessed whether a policy of not giving prophylactic platelet transfusions was as effective and safe as a policy of providing prophylaxis. METHODS We conducted this randomized, open-label, noninferiority trial at 14 centers in the United Kingdom and Australia. Patients were randomly assigned to receive, or not to receive, prophylactic platelet transfusions when morning platelet counts were less than 10×10(9) per liter. Eligible patients were persons 16 years of age or older who were receiving chemotherapy or undergoing stem-cell transplantation and who had or were expected to have thrombocytopenia. The primary end point was bleeding of World Health Organization (WHO) grade 2, 3, or 4 up to 30 days after randomization. RESULTS A total of 600 patients (301 in the no-prophylaxis group and 299 in the prophylaxis group) underwent randomization between 2006 and 2011. Bleeding of WHO grade 2, 3, or 4 occurred in 151 of 300 patients (50%) in the no-prophylaxis group, as compared with 128 of 298 (43%) in the prophylaxis group (adjusted difference in proportions, 8.4 percentage points; 90% confidence interval, 1.7 to 15.2; P=0.06 for noninferiority). Patients in the no-prophylaxis group had more days with bleeding and a shorter time to the first bleeding episode than did patients in the prophylaxis group. Platelet use was markedly reduced in the no-prophylaxis group. A prespecified subgroup analysis identified similar rates of bleeding in the two study groups among patients undergoing autologous stem-cell transplantation. CONCLUSIONS The results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding, as compared with no prophylaxis. A significant number of patients had bleeding despite prophylaxis. (Funded by the National Health Service Blood and Transplant Research and Development Committee and the Australian Red Cross Blood Service; TOPPS Controlled-Trials.com number, ISRCTN08758735.).

Peripheral Blood Hematopoietic Stem Cells for Transplantation of Hematological Diseases from Related, Haploidentical Donors after Reduced-Intensity Conditioning

In a multicenter collaboration, we carried out T cell-replete, peripheral blood stem cell (PBSC) transplantations from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplantation cyclophosphamide (Cy) as graft-versus-host disease (GVHD) prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50 mg/kg i.v. on days 3 and 4 after infusion of PBSC (mean, 6.4 × 10(6)/kg CD34(+) cells; mean, 2.0 × 10(8)/kg CD3(+) cells). The median times to neutrophil (500/μL) and platelet (>20,000/μL) recovery were 17 and 21 days respectively. All but 2 of the patients achieved full engraftment. The 1-year cumulative incidences of grade II and grade III acute GVHD were 53% and 8%, respectively. There were no cases of grade IV GVHD. The 2-year cumulative incidence of chronic GHVD was 18%. With a median follow-up of 509 days, overall survival and event-free survival at 2 years were 48% and 51%, respectively. The 2-year cumulative incidences of nonrelapse mortality and relapse were 23% and 28%, respectively. Our results suggest that PBSC can be substituted safely and effectively for bone marrow as the graft source for haploidentical transplantation after RIC.

The comprehensive care of sickle cell disease

Abstract: Millions of people across the world have sickle cell disease (SCD). Although the true prevalence of SCD in Europe is not certain, London (UK) alone had an estimated 9000 people with the disorder in 1997. People affected by SCD are best managed by a multidisciplinary team of professionals who deliver comprehensive care: a model of healthcare based on interaction of medical and non‐medical services with the affected persons. The components of comprehensive care include patient/parent information, genetic counselling, social services, prevention of infections, dietary advice and supplementation, psychotherapy, renal and other specialist medical care, maternal and child health, orthopaedic and general surgery, pain control, physiotherapy, dental and eye care, drug dependency services and specialist sickle cell nursing. The traditional role of haematologists remains to co‐ordinate overall management and liase with other specialities as necessary. Co‐operation from the affected persons is indispensable to the delivery of comprehensive care. Working in partnership with the hospital or community health service administration and voluntary agencies enhances the success of the multidisciplinary team. Holistic care improves the quality of life of people affected by SCD, and reduces the number as well as length of hospital admissions. Disease‐related morbidity is reduced by early detection and treatment of chronic complications. Comprehensive care promotes awareness of SCD among affected persons who are encouraged to take greater control of their own lives, and achieves better patient management than the solo efforts of any single group of professionals. This cost‐effective model of care is an option for taking haemoglobinopathy services forward in the new millennium.

Nonmyeloablative Peripheral Blood Haploidentical Stem Cell Transplantation for Refractory Severe Aplastic Anemia

New transplant approaches are urgently needed for patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor (UD) or who have failed UD or cord blood transplant. Patients with refractory SAA are at risk of later clonal evolution to myelodysplastic syndrome and acute leukemia. We report our pilot findings with haploidentical hematopoietic stem cell transplantation (haploHSCT) using uniform reduced-intensity conditioning with postgraft high-dose cyclophosphamide in 8 patients with refractory SAA or patients who rejected a prior UD or cord blood transplant. Six of 8 patients engrafted. Graft failure was associated with donor-directed HLA antibodies, despite intensive pre-HSCT desensitization with plasma exchange and rituximab. There was only 1 case of grade II skin graft-versus-host disease. We show that haploHSCT can successfully rescue refractory SAA patients who lack donor-directed HLA antibodies but not in the presence of donor-directed HLA antibodies. This novel protocol for haploHSCT for SAA has been adopted by the European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party for a future noninterventional, observational study to further evaluate its efficacy.

Rituximab is effective in the management of refractory autoimmune cytopenias occurring after allogeneic stem cell transplantation

Summary:Autoimmune haemolytic anaemia (AIHA), immune thrombocytopenia (ITP) and autoimmune neutropenia (AIN) are well-recognised complications of allogeneic stem cell transplantation (SCT), but have previously only been reported in the context of myeloablative conditioning regimens. Management of AIHA, ITP or AIN occurring after allogeneic SCT is unsatisfactory since they frequently prove refractory to conventional therapies including splenectomy. As a consequence, autoimmune cytopenias occurring after allogeneic SCT are associated with substantial morbidity and mortality. We report four patients who developed AIHA or ITP after allogeneic transplantation – three of which occurred after a reduced-intensity conditioning (RIC) regimen. All patients demonstrated a complete response to Rituximab, having failed to respond to conventional treatment including high-dose prednisolone and intravenous immunoglobulin (IVIg). We conclude that Rituximab can be a valuable agent in the management of autoimmune cytopenias occurring after allogeneic SCT and that autoimmune cytopenias may be a hitherto unrecognised complication of RIC regimens.

Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell–Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P < .001) and chronic (HR, 0.35; P < .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up.

Efficacy of bimonthly extracorporeal photopheresis in refractory chronic mucocutaneous GVHD

Extracorporeal photopheresis (ECP) has become a recognised treatment for steroid-refractory chronic GVHD (cGVHD), but the optimal frequency and duration of treatment are yet to be established. We report on 82 consecutive patients with mucocutaneous cGVHD who received a bimonthly regimen of ECP treatment for two consecutive days, which could be subsequently tapered to a monthly regimen depending on response. Patients were steroid-refractory, steroid-dependent or steroid-intolerant, and 29 (35%) had multiorgan involvement. The median duration of treatment was 330 days (42–987). The median number of ECP cycles was 15 (1.5–32). Response was assessed by clinical assessment and reduction in immunosuppression after 6 months. 69/82 (84%) had completed 6 months of ECP and 65/69 (94%) had ⩾50% improvement in symptoms and signs of cGVHD. A total of 77% of patients who completed 6 months of ECP had a reduction in immunosuppression dose and 80% had decreased their steroid dose (27.5% stopped, 30% had ⩾75% reduction, 17.5% had ⩾50% reduction and 25% had <50% reduction). OS at 3 years from the start of ECP was 69%. This study reports the largest series of patients receiving bimonthly ECP treatment for cGVHD, and confirms that ECP allows successful reduction of immunosuppression.

Guidelines for the diagnosis and management of adult myelodysplastic syndromes.

Sally B. Killick, Chris Carter, Dominic Culligan, Christopher Dalley, Emma Das-Gupta, Mark Drummond, Helen Enright, Gail L. Jones, Jonathan Kell, Juliet Mills, Ghulam Mufti, Jane Parker, Kavita Raj, Alexander Sternberg, Paresh Vyas, David Bowen and British Committee for Standards in Haematology The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, Hull and East Yorkshire Hospitals NHS Trust, Hull, Aberdeen Royal Infirmary, Aberdeen, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, Nottingham University Hospitals NHS Trust, Nottingham, Beatson West of Scotland Cancer Centre, Glasgow, UK, Tallaght Hospital Dublin, Trinity College Medical School, Dublin, Ireland, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, University Hospital of Wales, Cardiff, Worcestershire Acute Hospitals NHS Trust and Birmingham NHS Foundation Trust, Birmingham, Kings College Hospital NHS Foundation Trust, London, Northampton General Hospital NHS Trust, Northampton, Guys and St Thomas’ and Kings College Hospitals NHS Foundation Trusts, London, Great Western Hospitals NHS Foundation Trust, Swindon, Oxford University and Oxford University Hospitals NHS Trust, Oxford, and St. James’s Institute of Oncology, Leeds Teaching Hospitals, Leeds, UK

A parainfluenza-3 outbreak in a SCT unit: sepsis with multi-organ failure and multiple co-pathogens are associated with increased mortality

The estimated frequency of parainfluenza virus 3 (PIV-3) infections following haematopoietic SCT (HSCT) is 2–7%, whereas reported mortality ranges from 18 to 33%. We report a retrospective outcome analysis following an outbreak of PIV-3 infection in our transplant unit. A total of 16 HSCT patients developed PIV-3 infection. All patients had upper respiratory tract infection, whereas lower respiratory tract infection occurred in 8 patients. Overall, 13 patients were treated with aerosolised Ribavirin (2 g t.d.s. for 5 days) and i.v. Ig (0.5 g/kg) as per standard protocol. One patient refused treatment, whereas two patients with full immune reconstitution were not treated. Overall mortality was 62.5%. Sepsis with multi-organ failure and the presence of pulmonary co-pathogens were both significantly associated with PIV-3-related mortality. Our series confirms that high mortality is associated with PIV-3 infection in HSCT recipients. In patients who develop PIV-3 infection, despite strict enforcement of infection control policies, the best strategy might be careful risk assessment, with effective broad-spectrum anti-microbials in those who are at risk of secondary infection.

A multicentre UK study of GVHD following DLI: Rates of GVHD are high but mortality from GVHD is infrequent

DLIs are frequently used following haematopoietic SCT (HSCT) in patients with risk of relapse but data on GVHD following DLI are scarce. We report on 68 patients who received DLI following HSCT. Most patients developed GVHD following DLI (71%), which was acute in 22 patients (32%) almost half of whom had grade III–IV acute GVHD (aGVHD). Thirty patients (44%) developed cGVHD which followed aGVHD in four patients and was graded severe in nine patients. Corticosteroids were the most common first-line therapy for both acute and chronic GVHD. A wide range of second/third-line agents included cyclosporin, mycophenolate, tacrolimus, imatinib, infliximab and ECP. Relapse of initial malignancy occurred in 37%. Relapse was significantly less frequent in those receiving pre-emptive DLI. Relapse rates were also lower in those with GVHD (31%) than those without GVHD (50%), but this did not reach statistical significance. At 55 months post DLI, 34% of patients had died most commonly from relapse and 22% had on-going GVHD. Although GVHD was an important cause of morbidity post DLI (71%), only 6% died from GVHD. Although most patients develop GVHD post DLI and may require consecutive therapies, mortality from GVHD is infrequent. DLI remains an important option for relapse post transplant and manipulation of the GVT effect needs to be optimised to induce remission without morbidity from GVHD.